Lung cancer remains the leading cause of cancer-related mortality worldwide, yet its molecular pathogenesis is not fully understood.Here, we identify HADHB, encoding a mitochondrial -ketothiolase as a novel oncogene in lung cancer.Using a Hadhb PB/PB mouse model, we demonstrate that Hadhb deficiency in mice significantly suppresses K-Ras G12D -driven lung tumor progression by impairing cancer cell proliferation and enhancing apoptosis.Mechanistically, Hadhb loss induces proteotoxic endoplasmic reticulum (ER) stress, as evidenced by increased ATF6(N) and phosphorylation of eIF2 and subsequent upregulation of the pro-apoptotic factor CHOP. Crucially, knockdown of Chop partially restores oncogenic potential in Hadhb PB/PB mice and rescues the growth defect of HADHB-depleted cells, establishing CHOP as a key downstream mediator.Consistent with its oncogenic role, HADHB protein is upregulated in 52% (19/36) of human lung tumors compared to adjacent normal tissues, and low HADHB mRNA levels are correlated with good prognosis in lung cancer patients.Our findings unveil a previously unrecognized HADHB-CHOP regulatory axis in lung cancer progression and provide preclinical rationale for targeting mitochondrial metabolism in combination with ER stress modulators as a therapeutic strategy.
Dai et al. (Fri,) studied this question.